ACTIVATION OF THE ZONA INCERTA GABAERGIC CIRCUIT FOR THE TREATMENT OF PAIN HYPERSENSITIVITY IN PARKINSON’S DISEASE MICE MODEL

Pain is a prevalent undertreated non-motor symptom in Parkinson’s disease (PD). The zona incerta (ZI) is primarily an inhibitory subthalamic region involved in nociceptive neurotransmission. Previous studies demonstrated that the ZI is an important gamma-aminobutyric acid-ergic (GABAergic) source to the ventral tegmental area (VTA), but whether the ZI-VTA pathway participates in PD pain processing is still unclear. Given that deep brain stimulation targeting the ZI has demonstrated beneficial effects on pain perception in PD patients, we hypothesized that GABAergic signaling within the ZI may play a critical role in PD pain hypersensitivity. Our results showed that chemogenetic and optogenetic activation of ZI GABAergic neurons alleviated pain hypersensitivity in 6-OHDA-PD mouse model, whereas inhibition of these neurons was sufficient to induce pain hypersensitivity in control naïve mice. Furthermore, we demonstrated that projections from GABAergic neurons in the ZI to VTA are involved in regulating pain associated with PD. Activation of the ZI^GABA-VTA circuit alleviated pain symptoms; conversely, inhibiting activity within this circuit exacerbated both mechanical and thermal pain hypersensitivity. In conclusion, our results indicate that the ZI GABAergic neurons and their downstream projections to the VTA play crucial roles in modulating pain processing under both physiological conditions and during PD states. This research offers fresh perspectives on the PD pain mechanism. Considering our previous report indicating that stimulation of ZI GABAergic neurons improved motor performance in 6-OHDA-lesioned mice, we propose that the ZI may serve a dual regulatory function concerning both motor behavior and pain response associated with PD.